SLMS Academic Careers Office

26. Real-time and nanometre-scale visualisation of membrane perforation in pathogen attack and immune response

Supervisor Pair: Bart Hoogenboom / Alan Lowe and Helen Saibil Potential Student’s Home Department: Research Department of Structural and Molecular Biology

This project aims to visualize the assembly pathways of pore forming proteins and gain mechanistic insight in the effects of potential drugs and vaccines against bacterial toxins and of pore-forming protein deficiencies in the immune system.

Pore-forming proteins are crucial armaments in the continuous battle between organisms and their pathogens. In the course of their function, they assemble into oligomeric rings that puncture holes through their target membranes. For example, pore-forming bacterial toxins are proteins that perforate host cell membranes to release nutrients for the bacteria, to invade the host cell or to kill it. On the other hand, the immune system secretes pore-forming proteins to kill infected or cancerous cells, or invading pathogens, in the organism.

In particular the dynamics of membrane pore formation remain enigmatic, primarily due to the lack of high-resolution, dynamic pictures of membrane pore formation. This project will combine various microscopy techniques to obtain structural and dynamic information of proteins during their assembly and insertion into the membrane at high spatial and temporal resolution.

It will combine the highly interdisciplinary and complementary expertise of 3 academic supervisors: in atomic force microscopy (Dr Bart Hoogenboom, www.london-nano.com/our-people/academics/bart-hoogenboom), in single-molecule fluorescence microscopy (Dr Alan Lowe, www.arlowe.co.uk), and in electron microscopy of pore forming proteins (Prof Helen Saibil, people.cryst.bbk.ac.uk/~ubcg16z/Site/Home.html), and build on current work in their research groups, in the framework of an on-going BBSRC grant awarded to Hoogenboom and Saibil.

By elucidating the mechanism of membrane pore formation by pore-forming proteins, we aim to create new opportunities for drug design and testing: e.g., the prevention of pore formation by pneumolysin would be a significant advance in the treatment of bacterial pneumonia; the ability to control the pore-forming activity of perforin in the human immune system could be an important means of regulating the immune response during and after tissue/organ transplantation or could alleviate the perforin-dependent cytotoxicity in autoimmune diabetes.